Development of supramolecular anticoagulants with on-demand reversibility

Abstract

Drugs are administered at a dosing schedule set by their therapeutic index and termination of action is achieved by clearance and metabolism of the drug (hours to days for small molecules, weeks to months for biologics). In some cases, it is important to achieve a fast reversal of the drugs action to overcome dangerous side effects or in response to unforeseen events. A case in point is for anticoagulant drugs. Here we report a general strategy to achieve on-demand reversibility by leveraging supramolecular assembly of drug fragments and showcase the approach with thrombin-inhibiting anticoagulants. In our supramolecular drug design, the action of the drug is reinforced by a dynamic hybridisation of peptide nucleic acids (PNAs) between drug fragments. We show that this design enables the generation of very potent bivalent direct thrombin inhibitors (Ki 74 pM) and this inhibition can be reversed through the use of a PNA antidote. We demonstrate that these supramolecular inhibitors exhibit potent anticoagulant activity in vitro and in vivo and that this activity can also be reversed on demand.